The overall objective of this research continues to be a study of the effect of uremia on hepatic drug metabolism. In our previous studies, we have shown that in the rat acute renal failure induced by uranyl nitrate can lead to a pronounced inhibition of the hepatic first-pass metabolism of the Beta-adrenergic blocker 1-propranolol. Our data in the acute renal failure rat model are consistent with results of the earlier clinical studies in end stage renal failure patients. In our current application, we proposed to extend our pharmacokinetic investigations to determine if the degree of inhibitory effect of renal failure on the hepatic first-pass metabolism of 1-propranolol is related to the severity and/or duration of uremia. For this purpose, a chronic uremic animal model will be developed. We will also investigate whether chronic pretreatment with 1-propranolol can modulate the effect of renal failure on 1-propranolol metabolism. The second phase of our investigation will focus on identifying which of the primary metabolic pathways of 1-propranolol are affected in renal failure. In vitro metabolism studies will be carried out using the isolated rat hepatocyte. The final phase of proposed work will be directed at elucidating the mechanism(s) responsible for the inhibition of hepatic metabolism of 1-propranolol in uremia. Experiments will be designed to investigate the following postulated mechanisms: (1) presence of "endogenous inhibitor" in uremic blood; (2) alteration in the regulation and intrinsic activity of the hepatic drug metabolizing enzymes; (3) inhibition of 1-propranolol metabolism by metabolites which are retained in renal failure; and (4) regeneration of 1-propranolol by deconjugation of the glucuronide conjugate metabolite.